The broad objective of this continuation application is to detect and localize susceptibility loci in bipolar and related affective disorders. This goal will be attained by l. typing 39 extended high-density bipolar pedigrees with polymorphic DNA markers (these are previously ascertained medium-to-large sized kindreds with established cell lines on over 1000 informative members; the planned follow-up- see point 3 - will enlarge the sample to nearly 2000 individuals altogether); marker typing will focus on systematic scan of the genome, including candidate genes, with special emphasis on PCR based technology and microsatellite polymorphisms; 2. performing linkage analysis using a range of phenotypic and genetic models; 3. assessing the impact of diagnostic update and extension of pedigrees on the linkage results (this will be accomplished by a follow-up study of the pedigrees already identified using comprehensive clinical ratings and operational diagnostic criteria). Pending the results of the linkage analyses, long-range goals will include: identification and characterization of the disease gene(s); definition of linked disease forms on clinical and biological measures; elucidation of gene-environment interaction; and expansion of the pedigree roster to replicate linkage results, assess genetic heterogeneity, and generate, if appropriate, sufficient meiotic events for the cloning procedures. The availability of a unique series of pedigrees, coupled with recent advances in diagnostic procedures, molecular genetic techniques, and linkage analysis, holds promise for unraveling the genetic mechanisms that underlie some forms of major affective illness. This, in turn, may have 'important implications for the etiology, nosology, pathophysiology and, possibly, prevention and treatment of these disorders.